1. Field of the Invention
The present invention relates to novel biologically-active water soluble 3-substituted trioxanes and to their use as antiparasitic agents, particularly in malaria treatment.
2. Description of the Related Art
The trioxane drug artemisinin is an active anti-malarial constituent of the herb Artemisia annua L., Compositae. The herb has been known in China for almost 2000 years. Artemisinin was first isolated in 1972 and shown to be a sesquiterpene lactone with a peroxide moiety (1). The molecular structure was first reported in 1983 (2) and is shown in the following formula: ##STR3##
Several investigators have reported on the anti-malarial activity of artemisinin (3-5), and reviews of the chemistry, pharmacology and clinical applications of artemisinin have been published (6-8).
In addition to artemisinin, a number of related synthetic organic endoperoxides have been developed which have antimalarial activity. Saturated and unsaturated bicyclic endoperoxide compounds with antiparasitic/antimalarial activity are disclosed in U.S. Pat. Nos. 5,672,624 and 5,817,692 (both of which are hereby incorporated herein by reference), and 1,2,4 trioxane analogs of Artemisinin have been described (9). Avery et al. (10) described 3-substituted Artemisinin analogs, and noted that substitution with branched hydrocarbons lowered antimalarial potency appreciably.
A number of useful water-insoluble 3-substituted trioxanes were disclosed in prior U.S. application Ser. No. 08/758,661 (hereby incorporated herein by reference). Although effective, the use of these compounds for oral or IV administration is somewhat limited by their poor solubility in water.
Artelinic acid is a semisynthetic water soluble derivative of artemisinin of the formula ##STR4## which has also been found useful for the treatment of malaria. One disadvantage of this compound is that its production requires significant quantities of the crop Artemisia annua, which is used as starting material for the synthesis.
Biological evaluation of these compounds indicates that a number of them are effective antiparasitic agents. However, parasitic infections, particularly malaria, remain a serious and widespread public health problem, and concern exists about possible side effects of compounds developed to date. For example, neurotoxicity has been seen in rats which were administered high doses of artemether and in mouse neuroblastoma cells treated with dihydroartemesisin (11). For this reason, a need remains for the development of improved therapeutic agents for prevention and treatment of malaria.